The 5-HT.sub.7 receptor is the most recent addition to the burgeoning family of 5-HT receptors. 5-HT.sub.7 receptors have been cloned from rat, mouse, guinea pig, and human cDNA and exhibit a high degree of interspecies homology, (approximately 95%) but a low sequence homology with other 5-HT receptors (&lt;40%). The pharmacological profile of this receptor is unique yet consistent across species. Thus, high 5-HT.sub.7 receptor affinity is observed from 5-CT, 5-HT, 5-MeOT, and methiothepin, moderate affinity for 8-OHDPAT, clozapine, and ritanserin, and low affinity for pindolol, sumatriptan, and buspirone. Recent data have demonstrated the existence of four 5-HT.sub.7 splice variants in humans and three in rat (Heidmann, et al., J. Neurochem., 1997, 68, 1372-1381). Preliminary pharmacological comparison of the long (5-HT.sub.7a) and short (5-HT.sub.7b) forms of the receptor have revealed no substantial differences in receptor binding affinity (Jasper et al., J. Pharmocol., 1997, 120, 298). 5-HT.sub.7 receptors are positively coupled to adenylate cyclase when expressed in cell lines, native guinea pig hippocampus, and cultured vascular smooth muscle cells.
The greatest abundance of 5-HT.sub.7 mRNA is found in the brain where it is discretely located within thalamus, hypothalamus, and various limbic and cortical regions. Autoradiographic techniques confirm that the distribution of 5-HT.sub.7 receptor binding sites in rat and guinea pig brain matches, to a large extent, the mRNA distribution (To, et al., J. Pharmocol., 1995, 115, 107-116).
Preliminary data support that the 5-HT.sub.7 receptor may be involved in the pathophysiology of sleep disorders, depression, (Schwartz, et al., Adv. Int. Med. 1993, 38, 81-106) and schizophrenia (Roth, et al., J. Pharmacol. Exp. Ther., 1994, 268, 1403-1410). The 5-HT.sub.7 receptor stimulation has caused relaxation of the blood vessels in monkey (Leung, et al. Br. J. Pharmocol., 1996, 117, 926-930), dog (Cushing, et al. J. Pharmocol. Exp. Ther., 1996, 277, 1560-1566) and rabbit (Martin, et al., Br. J. Pharmocol., 1995, 114, 383). Therefore, the therapeutic utility of 5-HT.sub.7 receptor ligands requires the discovery of selective therapeutic agents. The present invention discloses novel 5-HT.sub.7 receptor antagonists.